
Appendix II
Proposed Re-evaluation Decision - PRVD2019-10
Page 41
Study Type/
Animal/PMRA #
CD-1 Mouse
PMRA #1164978
≥5000 ppm (838/964 mg/kg bw/day): hunched posture, few or no feces,
↓Hgb, ↓ Hct, ↑ platelets, ↑ wc, ↑ BUN, ↑ rel liver wt, renal effects (tubular
nephrosis, dilation of renal tubules and pelvis, focal mineralization); ↑
mortality, ↓ bw, ↓ bwg, ↑ rel adrenal gland wt, ↓ MCV, ↓ MCH, ↑ AST, ↑
ALT, thymic lymphoid depletion, bone marrow myeloid hyperplasia, ↑
spleen pigmentation (♂); thin appearance, ↓ RBC, ↑ cholesterol, ↑
phospholipids, ↑ abs liver wt (♀).
10,000 ppm (2035/2345 mg/kg bw/day): myeloid hyperplasia of bone
marrow, cardiomyopathy, thymic atrophy; ↓ RBC, mortality, ↓ bw, thymic
lymphoid depletion, ↑ spleen pigmentation, extra medullary hematopoiesis
(capsule)
Beagle Dog
PMRA #1143898
NOAEL = 100 mg/kg bw/day (♀); 300 mg/kg bw/day (♂)
≥300 mg/kg bw/day: ↑ liver wt; hepatocellular enlargement, ↑ cholesterol, ↑
phospholipid (♀).
1000 mg/kg bw/day: hepatic cytoplasmic changes (eosinophilic bodies, ↑ in
smooth endoplasmic reticulum proliferation, dilation of endoplasmic
reticulum); hepatocellular enlargement (♂).
(capsule)
Beagle Dog
PMRA #1143882, 2704560,
1159076
NOAEL = 30 mg/kg bw/day (♂); 100 mg/kg bw/day (♀)
≥30 mg/kg bw/day: ↑ rel liver wt (♂).
≥100 mg/kg bw/day: ↓ bwg, ↑ cholesterol, ↑ liver wt; ↓bw, ↑ triglycerides, ↑
ALK in one animal (♂)
≥300 mg/kg bw/day: ↑ ALK; thin appearance, ↑ platelets, submucosal
fibrosis of the gall bladder (♂); ↓ bw, ↑ triglycerides, ↑ rel kidney wt, ↑
thyroid wt (♀).
1000 mg/kg bw/day: salivation, diarrhea, emesis, ↑ ALT, centriacinar
fibrosis, bile duct hyperplasia, active chronic inflammatory infiltrate,
submucosal edema of the gall bladder; 2 mortalities (sacrificed due to
toxicity), bw loss, ↑ prothrombin time, ↑ AST, ↑ bilirubin, ↑ urinary volume,
↓ pH, nodular hyperplasia, (♂); ↑ platelets, submucosal fibrosis of the gall
(capsule)
Beagle Dog
≥3 mg/kg bw/day: slight ↑ platelets (♂).
10 mg/kg bw/day: slight ↑ platelets (♀).
Chronic Toxicity/Oncogenicity Studies
(dietary)
CD-1 Mouse
PMRA #1143912, 1143930,
1159013, 1169747, 2704561
NOAEL = 120 ppm (16 mg/kg bw/day) (♂); 600 ppm (107 mg/kg
bw/day)(♀)
≥120 ppm (16/21 mg/kg bw/day: hunched posture.
≥600 ppm (79/107 mg/kg bw/day): ↓ survival after week 64, ↑ severity of
amyloidosis in kidneys, thyroid, parathyroid and stomach of decedents (♂).
3000 ppm (413/530 mg/kg bw/day): ↓ bw, granular/pitted/rough kidneys,